CAREER: Neuronal Data Assimilation Tools and Models for Understanding Circadian Rhythms

职业：用于理解昼夜节律的神经元数据同化工具和模型

• 批准号: 1555237
• 负责人: Casey Diekman
• 金额: $ 42.97万
• 依托单位: New Jersey Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1555237&HistoricalAwards=false
• 关键词: CAREER; Neuronal; Data; Assimilation; Tools

Human beings possess an internal timekeeping mechanism known as the circadian clock that aligns physiological processes with the appropriate time of day, for example by stimulating the release of the sleep-promoting hormone melatonin in the evening and the wake-promoting hormone cortisol in the morning. Misalignment of the circadian clock with respect to 24-hour environmental cycles occurs after rapid travel across time zones and leads to symptoms of jet lag including sleep disturbances, digestive problems, and decreased cognitive performance. The circadian clock is highly conserved across animal species, and there are many similarities in the genes and neural circuits involved in the circadian systems of humans and the fruit fly Drosophila. The goal of this project is to obtain a mathematical understanding of the biology underlying jet lag by developing a detailed model of the circadian clock in Drosophila and then systematically analyzing how the clock is disrupted by sudden changes in the timing of the external light-dark cycle. The predictions of the computational model will then be tested in flies through experiments that simulate transmeridian travel. This project will also create new tools for building mathematical models directly from observed data by bringing together techniques from applied mathematics, statistics, and neuroscience. A unique graduate-level course at the intersection of these fields will be developed. Graduate, undergraduate, and community college students will be involved in this research and obtain interdisciplinary training. The undergraduate and community college students will form integrated summer research project teams. Community college students will be recruited to enroll in an undergraduate-level mathematical modeling course at the New Jersey Institute of Technology and will receive mentorship on pursuing four-year STEM degree program opportunities.This project focuses on the interface between dynamical systems and statistical data analysis in the context of neuronal modeling. The research goal of this project is to develop novel data assimilation methodologies for inferring models of neuronal dynamics directly from time-course data that enable insights into biological mechanisms. Specifically, this project will create new data assimilation tools to identify and parameterize neurophysiological models from voltage traces recorded from the Drosophila circadian (~24-hour) clock network. This research effort will address two major gaps in the mathematical/computational neuroscience field: a scarcity of methods for inferring parameters of unobserved ionic currents from measurements of membrane voltage alone, and a lack of models that link molecular, cellular, and behavioral scales. This will be accomplished by developing a method to design stimulus protocols for use in data assimilation algorithms that optimally unmask the dynamics of unobservable neuronal variables and improve inference of electrophysiological models and parameters. The method will be used to build a model of the Drosophila clock network that links circadian rhythms in gene expression to changes in neuronal activity and behavioral outputs. These models will be used to analyze how the internal circadian oscillator re-entrains following phase shifts in the external light-dark cycle. More generally, this work aims to elucidate fundamental aspects of synchronization and entrainment in oscillatory systems.

人类拥有一种被称为生物钟的内部计时机制，它将生理过程与一天中的适当时间保持一致，例如通过在晚上刺激促进睡眠的激素褪黑素的释放，在早上刺激促进清醒的激素皮质醇的释放。生物钟相对于24小时环境周期的错位发生在快速跨越时区后，并会导致时差症状，包括睡眠障碍、消化问题和认知能力下降。生物钟在动物物种中高度保守，人类和果蝇的生物钟系统中涉及的基因和神经电路有许多相似之处。这个项目的目标是通过建立果蝇生物钟的详细模型，然后系统地分析外部明暗周期的突然变化是如何扰乱生物钟的，从而获得对时差背后的生物学原理的数学理解。然后，计算模型的预测将通过模拟跨子午线旅行的实验在苍蝇身上进行测试。该项目还将创建新的工具，通过将应用数学、统计学和神经科学的技术结合在一起，直接从观测数据建立数学模型。将在这些领域的交汇点上开发一门独特的研究生课程。研究生、本科生和社区学院的学生将参与这项研究，并获得跨学科的培训。本科生和社区大学生将组成综合暑期研究项目团队。社区学院的学生将被招募到新泽西理工学院参加本科水平的数学建模课程，并将在攻读四年制STEM学位课程机会方面获得指导。本项目侧重于在神经元建模的背景下动态系统和统计数据分析之间的接口。该项目的研究目标是开发新的数据同化方法，用于直接从时间进程数据推断神经元动力学模型，从而能够深入了解生物机制。具体地说，该项目将创建新的数据同化工具，从果蝇昼夜(~24小时)时钟网络记录的电压轨迹中识别神经生理学模型并将其参数化。这项研究工作将解决数学/计算神经科学领域的两个主要空白：缺乏仅根据膜电压测量来推断未观察到的离子电流参数的方法，以及缺乏将分子、细胞和行为尺度联系起来的模型。这将通过开发一种方法来设计刺激方案，用于数据同化算法，以最佳地揭示不可观测的神经元变量的动力学，并改进电生理模型和参数的推断。该方法将用于建立果蝇时钟网络的模型，该模型将基因表达的昼夜节律与神经元活动和行为输出的变化联系起来。这些模型将被用来分析内部昼夜节律振荡器如何跟随外部明暗循环中的相移而重新进入。更广泛地说，这项工作旨在阐明振荡系统中同步和卷吸的基本方面。